Central Retinal Vein Occlusion, Macular Edema
Conditions
Keywords
Ophthalmology, Ranibizumab, Central Retinal Vein Occlusion
Brief summary
The present study provided additional efficacy and safety data for 0.5-mg ranibizumab using as needed (PRN) dosing over 24 months in patients with visual impairment due to macular edema secondary to Central Retinal Vein Occlusion (CRVO). Spectral domain high-definition optical coherence tomography (OCT) images was analyzed to gain insights into predictive factors for disease progression and the possibility of reduced monitoring was assessed in Year 2. The results of this open-label study provided long-term safety and efficacy data to further guide recommendations on the use of ranibizumab in this indication.
Interventions
Patients will receive the first dose at Baseline, as an intravitreal injection with a standard dose of 0.5 mg/0.05 ml. Patients will receive at least 3 study treatments at monthly intervals (Day 1, Month 1 and Month 2). The last mandatory dose during treatment initiation will be administered approximately 60 days after the first study treatment. If there is no improvement in VA over the course of the first 3 injections, continued treatment is not recommended and the patient may receive alternative treatment at the investigator's discretion.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients ≥ 18 years of age * Diagnosis of visual impairment exclusively due to ME secondary to CRVO * BCVA score at Screening and Baseline between 73 and 19 letters Early Treatment Diabetic Retinopathy Study (ETDRS), inclusively (approximate Snellen chart equivalent of 20/40 and 20/400)
Exclusion criteria
* Uncontrolled blood pressure defined as systolic value of \> 160 mm Hg or diastolic value of \> 100 mm Hg at Screening or Baseline. * Any active periocular or ocular infection or inflammation at Screening or Baseline in either eye * Uncontrolled glaucoma at Screening or Baseline or diagnosed within 6 months before Baseline in either eye * Use of any systemic antivascular endothelial growth factor (anti-VEGF) drugs within 6 months before Baseline (eg, sorafenib \[Nexavar®\], sunitinib \[Sutent®\], bevacizumab \[Avastin®\])
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Best Corrected Visual Acuity (BCVA) at Month 12 Compared to Baseline | Baseline to month 12 | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Average Change in Best Corrected Visual Acuity (BCVA From Baseline Month 12 and Month 24 | Baseline and Month 1 to 12 or Month 24 | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. Mean Average Change: for each patient, first average change is calculated as the average of the changes from baseline to Month 1 over Month 12 (or Month 24). Then, mean average change is calculated as the average of average changes across all patients. |
| Mean Average Change in BCVA From First Treatment Interruption (Due to BCVA Stabilization) to Month 12 and Month 24 | Month 12 and Month 24 | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. Stability in visual acuity after treatment interruption indicates longer duration of the drug efficacy |
| Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | Month 12 and Month 24 | BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters of visual acuity at month 12 as compared with baseline |
| Mean Change in Best Corrected Visual Acuity (BCVA) at Month 24 Compared to Baseline | Baseline to Month 24 | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement |
| Mean Change in Central Reading Center (CRC)-Assessed Central Subfield Thickness (CSFT) From Month 12 and Month 24 Compared to Baseline | Baseline, Month 12 and Month 24 | Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation |
| Mean Change in Patient-reported Outcomes in NEI-VFQ-25 Composite and Subscale Scores at Month 12 and Month 24 Compared to Baseline | Month 12 and Month 24 | The survey consists of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranges from 0 (worst) to 100 which indicates the best possible response. The composite score and score of each of each construct also range from 0 to 100 as they are calculated as total scores divided by the number of questions. The higher the values of total scores represent better outcome. Scores per visit and of the change descriptively by visit. |
| Number of Patients With a BCVA Value of ≥ 73 Letters (Approximate 20/40 Snellen Chart Equivalent) at Month 12 and Month 24 | Month 12 and Month 24 | Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart at baseline and month 12 while participants were in a sitting position at a testing distance of 4 meters. The range of EDTRS is 0 to 100 letters. BCVA above 73 letters at month 12 and month 24 indicates a positive outcome. |
Countries
Australia, Austria, Canada, Czechia, Denmark, Greece, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
No data were excluded from the Full Analysis Set (FAS )analyses because of protocol deviations.
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab Arm Intravitreal injection with standard dose of 0.5 mg/0.05mL PRN | 357 |
| Total | 357 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Death | 5 |
| Overall Study | Lost to Follow-up | 8 |
| Overall Study | Physician Decision | 8 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | Ranibizumab Arm |
|---|---|
| Age, Continuous | 65.5 Years STANDARD_DEVIATION 12.68 |
| Sex: Female, Male Female | 128 Participants |
| Sex: Female, Male Male | 229 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 244 / 357 |
| serious Total, serious adverse events | 64 / 357 |
Outcome results
Primary
Mean Change in Best Corrected Visual Acuity (BCVA) at Month 12 Compared to Baseline
Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement
Time frame: Baseline to month 12
Population: The Full analysis set (FAS) with use of Last Observation Carried Forward (LOCF) consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. One patient was excluded from the FAS for not having ≥ 1 post-baseline study eye VA assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab Arm | Mean Change in Best Corrected Visual Acuity (BCVA) at Month 12 Compared to Baseline | 12.3 Letters | Standard Deviation 16.72 |
Secondary
Mean Average Change in BCVA From First Treatment Interruption (Due to BCVA Stabilization) to Month 12 and Month 24
Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. Stability in visual acuity after treatment interruption indicates longer duration of the drug efficacy
Time frame: Month 12 and Month 24
Population: Full analysis set with use of LOCF consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. The number of patients shown was with a value at treatment interruption and an average for the post treatment interruption visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Arm | Mean Average Change in BCVA From First Treatment Interruption (Due to BCVA Stabilization) to Month 12 and Month 24 | Month 12 (n=310) | -2.7 Letters | Standard Deviation 8.04 |
| Ranibizumab Arm | Mean Average Change in BCVA From First Treatment Interruption (Due to BCVA Stabilization) to Month 12 and Month 24 | Month 24 (n=331) | -2.5 Letters | Standard Deviation 8.95 |
Secondary
Mean Average Change in Best Corrected Visual Acuity (BCVA From Baseline Month 12 and Month 24
Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. Mean Average Change: for each patient, first average change is calculated as the average of the changes from baseline to Month 1 over Month 12 (or Month 24). Then, mean average change is calculated as the average of average changes across all patients.
Time frame: Baseline and Month 1 to 12 or Month 24
Population: The Full analysis set (FAS) with use of Last Observation Carried Forward (LOCF) consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. One patient was excluded from the FAS for not having ≥ 1 post-baseline study eye VA assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Arm | Mean Average Change in Best Corrected Visual Acuity (BCVA From Baseline Month 12 and Month 24 | Month 12 | 11.8 letters | Standard Deviation 12.44 |
| Ranibizumab Arm | Mean Average Change in Best Corrected Visual Acuity (BCVA From Baseline Month 12 and Month 24 | Month 24 | 12.1 letters | Standard Deviation 14.2 |
Secondary
Mean Change in Best Corrected Visual Acuity (BCVA) at Month 24 Compared to Baseline
Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement
Time frame: Baseline to Month 24
Population: The Full analysis set (FAS) with use of Last Observation Carried Forward (LOCF) consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. One patient was excluded from the FAS for not having ≥ 1 post-baseline study eye VA assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab Arm | Mean Change in Best Corrected Visual Acuity (BCVA) at Month 24 Compared to Baseline | 12.1 Letters | Standard Deviation 18.6 |
Secondary
Mean Change in Central Reading Center (CRC)-Assessed Central Subfield Thickness (CSFT) From Month 12 and Month 24 Compared to Baseline
Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation
Time frame: Baseline, Month 12 and Month 24
Population: The Full analysis set (FAS) with use of Last Observation Carried Forward (LOCF) consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. No data were excluded from the FAS analyses because of protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Arm | Mean Change in Central Reading Center (CRC)-Assessed Central Subfield Thickness (CSFT) From Month 12 and Month 24 Compared to Baseline | Change from Baseline at Month 12 | -335.7 Microns | Standard Deviation 285.02 |
| Ranibizumab Arm | Mean Change in Central Reading Center (CRC)-Assessed Central Subfield Thickness (CSFT) From Month 12 and Month 24 Compared to Baseline | Change from Baseline at Month 24 | -349.1 Microns | Standard Deviation 275.35 |
Secondary
Mean Change in Patient-reported Outcomes in NEI-VFQ-25 Composite and Subscale Scores at Month 12 and Month 24 Compared to Baseline
The survey consists of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranges from 0 (worst) to 100 which indicates the best possible response. The composite score and score of each of each construct also range from 0 to 100 as they are calculated as total scores divided by the number of questions. The higher the values of total scores represent better outcome. Scores per visit and of the change descriptively by visit.
Time frame: Month 12 and Month 24
Population: The Full analysis set (FAS) with use of Last Observation Carried Forward (LOCF) consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. The number of patients shown was with a value for both baseline and the post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Arm | Mean Change in Patient-reported Outcomes in NEI-VFQ-25 Composite and Subscale Scores at Month 12 and Month 24 Compared to Baseline | Change from baseline at Month 12 | 6.9 Score on a scale | Standard Deviation 12.65 |
| Ranibizumab Arm | Mean Change in Patient-reported Outcomes in NEI-VFQ-25 Composite and Subscale Scores at Month 12 and Month 24 Compared to Baseline | Change from baseline at Month 24 | 6.6 Score on a scale | Standard Deviation 14.03 |
Secondary
Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters of visual acuity at month 12 as compared with baseline
Time frame: Month 12 and Month 24
Population: The Full analysis set (FAS) with use of Last Observation Carried Forward (LOCF) consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. No data were excluded from the FAS analyses because of protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 1 (Month 12) | 296 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 5 (Month 12) | 275 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 10 (Month 12) | 227 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 15 (Month 12) | 175 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 30 (Month 12) | 32 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 1 (Month 24) | 290 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 5 (Month 24) | 265 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 10 (Month 24) | 224 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 15 (Month 24) | 175 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline to Month 12 and Month 24 in the Study Eye | BCVA improvement of >= 30 (Month 24) | 44 Letters |
Secondary
Number of Patients With a BCVA Value of ≥ 73 Letters (Approximate 20/40 Snellen Chart Equivalent) at Month 12 and Month 24
Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart at baseline and month 12 while participants were in a sitting position at a testing distance of 4 meters. The range of EDTRS is 0 to 100 letters. BCVA above 73 letters at month 12 and month 24 indicates a positive outcome.
Time frame: Month 12 and Month 24
Population: The Full analysis set (FAS) with use of Last Observation Carried Forward (LOCF) consisted of all patients who received at least 1 administration of study treatment and had at least 1 post-baseline assessment for BCVA in the study eye. No data were excluded from the FAS analyses because of protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab Arm | Number of Patients With a BCVA Value of ≥ 73 Letters (Approximate 20/40 Snellen Chart Equivalent) at Month 12 and Month 24 | Month 12 | 169 Letters |
| Ranibizumab Arm | Number of Patients With a BCVA Value of ≥ 73 Letters (Approximate 20/40 Snellen Chart Equivalent) at Month 12 and Month 24 | Month 24 | 161 Letters |